Last updated Jan. 17, 2022, by Marisa Wexler, MS
 Fact-checked by Ana de Barros, PhD
Simufilam (formerly PTI-125 and sumifilam) is an experimental therapy that Cassava Sciences is developing for Alzheimer’s disease. The investigational small molecule is designed to ease patients’ cognitive symptoms.
How does simufilam work?
The proper folding of proteins is vital for them to work correctly, and abnormal protein folding is believed to play a central role in the development of Alzhiemer’s. Misfolded proteins clump together in the brain, forming plaques or clumps that may impede brain function, damage nerve cells, and prompt inflammation.
Filamin A is one of the misfolded proteins in Alzheimer’s. It is a scaffolding protein, a type that helps the proper folding of other proteins.
Correctly functioning filamin A is essential for the proper folding and working of amyloid-beta and tau, two proteins that play a role in the development of Alzheimer’s. In its altered form, filamin A prevents the proper folding of the amyloid-beta and tau proteins. This causes them to aggregate, or clump, and form plaques and tangles in the brain. Misfolded filamin A also disrupts how nerve cells work, leading to neurodegeneration in people with the disease.
Simufilam is an investigational small molecule that targets misfolded filamin A protein. It binds to this filamin A and aims to restore its function, potentially alleviating disease symptoms.
Simufilam in clinical trials
A Phase 1 clinical trial (NCT03784300) involving healthy volunteers, completed in 2018, evaluated simufilam’s safety and pharmacokinetics, or its movement in the body. The results showed it was safe and well tolerated.
An open-label Phase 2a clinical trial (NCT03748706), which wrapped up in 2019, investigated the safety and pharmacokinetics of simufilam in 12 patients with mild to moderate Alzheimer’s. Study results showed that 28 days of simufilam treatment, at 100 milligrams (mg) twice daily, was well tolerated and that patients had markedly lower disease-specific biomarkers of inflammation and nerve damage in the brain.
Cassava then launched a randomized, placebo-controlled Phase 2b clinical trial (NCT04079803) that enrolled 64 people with mild to moderate Alzheimer’s, ages 50 to 85, at several U.S. sites. Participants were randomly assigned to receive either 50 mg or 100 mg oral tablets of simufilam, or a placebo, twice a day. The trial’s main goal was to assess whether the treatment lowered levels of Alzheimer’s-related biomarkers in participants’ cerebrospinal fluid (CSF, the fluid around the brain and spinal cord) after 28 days.
Initial results, announced in 2020, showed no significant difference in biomarker levels between simufilam-treated patients and those given placebo — but further analysis showed that this lack of difference was probably because there was substantial variation in biomarker levels even in the placebo group. An updated analysis announced later that year indicated that simufilam treatment significantly reduced levels of markers of nerve damage and inflammation and was generally safe and well tolerated.
Cassava is now running two Phase 3 clinical trials, RETHINK-ALZ (NCT04994483) and REFOCUS-ALZ (NCT05026177), to test whether simufilam treatment can slow the decline in cognition in people with mild to moderate Alzheimer’s, ages 50 to 87. In RETHINK-ALZ, about 750 participants will be given either 100 mg simufilam or placebo twice daily for about a year while REFOCUS-ALZ aims to recruit about 1,000 patients who will receive 50 mg or 100 mg simufilam, or placebo, for about two years.
Both studies are using the same primary measures of efficacy: changes over time in Alzheimer’s Disease Assessment Scale-Cognitive Subscale (ADAS-Cog), which measures cognition, and Alzheimer’s Disease Cooperative Study — Activities of Daily Living (ADCS-ADL), which assesses the ease of performing day-to-day tasks. Both RETHINK-ALZ and REFOCUS-ALZ began enrolling participants in late 2021.
Cassava also is running an open-label Phase 2 trial (NCT04388254) that is enrolling 150 patients who have participated in prior clinical studies of simufilam. All participants in this trial are taking 100 mg simufilam twice daily. An interim analysis on the first 50 evaluable patients indicated that the treatment improved cognition and behavior after six months.
Specifically, compared with the study’s start, mean scores on the ADAS-Cog improved by 10% while scores on the Neuropsychiatric Inventory (NPI), which assesses dementia-related behavioral symptoms, improved by 29%.
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